{"gene":"IL20RA","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"IL-24 (MDA-7/MOB-5) binds to and signals through two heterodimeric receptor complexes: IL-22R1/IL-20R2 and IL-20R1/IL-20R2 (the latter being the same receptor used by IL-20). COS cells transfected with either receptor heterodimer bind IL-24 with similar saturation kinetics, and IL-24 binding to either receptor complex on keratinocytes or ectopically expressing BHK cells activates STAT transcription factors.","method":"Ligand binding assay (COS cell transfection, saturation kinetics), STAT activation assay in keratinocytes and BHK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated in multiple cell contexts, STAT activation confirmed, replicated across cell types in a single rigorous study","pmids":["11706020"],"is_preprint":false},{"year":2011,"finding":"The IL-20–IL-20R1–IL-20R2 ternary complex was successfully purified and crystallized, forming a 1:1:1 complex that diffracted to 3 Å resolution, establishing the stoichiometry and feasibility of structural determination of the IL-20/IL-20R1/IL-20R2 signaling complex.","method":"Protein purification, crystallization, preliminary X-ray diffraction analysis","journal":"Acta crystallographica. Section F, Structural biology and crystallization communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure reported at preliminary stage (no full structure published in this abstract), single study","pmids":["22232181"],"is_preprint":false},{"year":2014,"finding":"IL-20 signals through IL-20R1-containing receptor complexes to activate hepatic stellate cells, upregulate TGF-β1, TNF-α, and type I collagen expression, promote HSC proliferation and migration, and induce hepatocyte cell-cycle arrest. IL-20R1-deficient mice were protected from both short-term and long-term CCl4-induced liver injury, establishing IL-20R1 as required for IL-20-mediated hepatic fibrosis.","method":"Anti-IL-20R1 monoclonal antibody (51D) treatment in vivo; IL-20R1-deficient mouse model; in vitro HSC activation assays; CCl4 liver injury model","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout (IL-20R1-deficient mice) combined with antibody blockade and in vitro functional assays across multiple cell types and in vivo models","pmids":["24763901"],"is_preprint":false},{"year":2019,"finding":"IL-24 binding to receptor 1 subunits (IL-20R1 and IL-22R1) is governed by a flexible region around residue T198 in IL-24; a single back-engineered wild-type residue (T198) restored 80% of binding affinity to IL-20R1 and IL-22R1 and restored signaling capacity, while affinity to IL-20R2 was preserved in stabilized IL-24 variants.","method":"Protein engineering (PROSS algorithm-based mutagenesis), biophysical binding assays to extracellular receptor domains, signaling capacity assay, crystal structure of IL-24 variant (PDB 6GG1)","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure determination plus site-directed mutagenesis with functional rescue, multiple orthogonal methods in one study","pmids":["31152679"],"is_preprint":false},{"year":2019,"finding":"In intestinal lymphatic endothelial cells from Crohn's disease patients, mTOR signaling drives upregulation of IL-20RA, and IL-20RA-mediated intracellular signaling is required for LPMC transmigration through the lymphatic endothelial barrier; blocking this pathway reduced leukocyte trafficking.","method":"Transcriptomic profiling of isolated human intestinal lymphatic endothelial cells, transwell co-culture transmigration assay, mTOR pathway manipulation","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional transmigration assay with pathway inhibition, single lab, human primary cells","pmids":["31426584"],"is_preprint":false},{"year":2021,"finding":"IL-20RA activates the JAK1–STAT3–SOX2 signaling axis in breast cancer cells, enhancing stemness (increased SP proportion, ALDH activity, sphere formation, Sox2/Oct4 expression) and promoting PD-L1 expression while reducing CD8+ T cell and NK cell recruitment and increasing MDSC proportions in the tumor microenvironment.","method":"Gain- and loss-of-function (overexpression and knockdown) in breast cancer cell lines and mouse models; ELISA; flow cytometry; in vivo tumor initiation and metastasis assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with multiple orthogonal phenotypic readouts and in vivo validation, single lab","pmids":["33456560"],"is_preprint":false},{"year":2021,"finding":"MIR452 directly targets IL-20RA (confirmed by luciferase reporter assay); overexpression of MIR452 decreases IL-20RA protein and downstream JAK1 and STAT3 (but not STAT1), and IL-20RA knockdown similarly decreases JAK1 and STAT3, placing IL-20RA upstream of JAK1–STAT3 (but not JAK1–STAT1) signaling in colorectal cancer cells.","method":"Luciferase reporter assay (miR-452 targeting IL-20RA 3'UTR), siRNA knockdown, Western blot, RT-PCR","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase assay plus knockdown with defined downstream pathway readouts, single lab","pmids":["34283251"],"is_preprint":false},{"year":2021,"finding":"IL-20R1 mediates hematoma resolution after germinal matrix hemorrhage via the IL-20R1/ERK/Nrf2 pathway: rIL-19 treatment upregulated ERK, Nrf2, and CD163 expression, while IL-20R1 CRISPR knockdown abolished these effects, demonstrating that IL-20R1 is required for rIL-19-mediated scavenger receptor CD163 upregulation.","method":"In vivo rat GMH model; intranasal rIL-19 administration; IL-20R1 CRISPR knockdown (intracerebroventricular); Western blot; immunohistochemistry; hemoglobin assay; neurobehavioral testing","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown (CRISPR) of IL-20R1 with rescue/blockade, multiple outcome measures, single lab in vivo model","pmids":["33532035"],"is_preprint":false},{"year":2018,"finding":"CRISPR/Cas9 deletion of a genomic region containing variant rs6927172 (located ~140 kb upstream of TNFAIP3) altered expression of IL-20RA; EMSA and chromatin conformation capture demonstrated that the DNA element carrying rs6927172 physically interacts with the IL-20RA locus and that the risk allele enhances NFκB binding and chromatin looping to regulate IL-20RA expression.","method":"CRISPR/Cas9 knockout in HEK293T cells, EMSA, Western blot, chromatin conformation capture (3C), TALE-based transcriptional analysis","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (CRISPR deletion, EMSA, 3C chromatin looping) establishing regulatory mechanism, single lab","pmids":["29483615"],"is_preprint":false},{"year":2022,"finding":"In grass carp, IL-20R1 (CiIL-20R1/CRFB8) but not IL-20R2 is responsible for STAT3 phosphorylation downstream of IL-20 signaling; co-immunoprecipitation showed that IL-20 binds CiIL-20R2 but not CiIL-20R1, suggesting a division of labor where R2 captures ligand and R1 transduces the intracellular STAT3 signal. Structural modeling showed conservation of key residues with human IL-20R1.","method":"Co-immunoprecipitation, STAT3 phosphorylation assay, structural modeling","journal":"Fish & shellfish immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and functional signaling assay in fish ortholog with structural conservation noted; single lab, non-mammalian model","pmids":["36414129"],"is_preprint":false},{"year":2024,"finding":"In fish (crucian carp hybrid), WR-IL-26 forms a complex with both WR-IL10R2 and WR-IL20R1 (co-immunoprecipitation); silencing WR-IL20R1 via RNA interference significantly attenuated IL-26-mediated JAK1–STAT3 pathway activation and reduced gut mucosal barrier protection against Aeromonas hydrophila infection.","method":"Co-immunoprecipitation, RNA interference knockdown, JAK1–STAT3 signaling assay, in vivo bacterial challenge","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus RNAi loss-of-function with defined signaling readout, single lab, non-mammalian model (fish ortholog)","pmids":["39154973"],"is_preprint":false},{"year":2025,"finding":"IL-20RA knockdown in nephroblastoma (Wilms tumor) cells increased apoptosis and ferroptosis, and IL-20RA promotes epithelial-mesenchymal transition through the STAT3/SNAIL pathway.","method":"siRNA knockdown, apoptosis/ferroptosis assays, EMT marker analysis, Western blot","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with phenotypic readout, pathway placement inferred without full mechanistic validation; abstract-level description","pmids":["40185911"],"is_preprint":false},{"year":2024,"finding":"In pig Sertoli cells, IL-20RA knockdown (siRNA) affected mitochondrial superoxide production and catalase secretion, identifying IL-20RA as a regulator of mitochondrial antioxidant capacity in these cells.","method":"siRNA knockdown, ROS measurement, mitochondrial superoxide assay, catalase activity assay, transcriptomic analysis","journal":"Antioxidants (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method knockdown in non-human (pig) cells, single lab, limited mechanistic pathway detail in abstract","pmids":["39765872"],"is_preprint":false}],"current_model":"IL-20RA (IL-20R1/ZCYTOR7) is a cytokine receptor subunit that forms heterodimeric signaling complexes with IL-20R2 (binding IL-19, IL-20, and IL-24) and with IL-22R1 (binding IL-24); upon ligand binding, IL-20R1 provides the long intracellular domain responsible for activating JAK1–STAT3 (and to a lesser extent STAT1) signaling, driving downstream transcriptional programs including SOX2, PD-L1, and Nrf2 in contexts ranging from skin and liver homeostasis to cancer stemness, immune regulation, and inflammatory disease."},"narrative":{"mechanistic_narrative":"IL20RA (IL-20R1/ZCYTOR7) is a cytokine receptor subunit that assembles heterodimeric signaling complexes to transduce IL-19, IL-20, and IL-24 family signals into JAK1–STAT3 transcriptional programs governing epithelial homeostasis, inflammation, and tumor biology [PMID:11706020, PMID:33456560]. It pairs with IL-20R2 to form ligand-binding heterodimers: IL-24 signals through both IL-20R1/IL-20R2 and IL-22R1/IL-20R2 complexes, with IL-20R1 binding ligand and activating STAT transcription factors in keratinocytes and other cells [PMID:11706020], and the IL-20/IL-20R1/IL-20R2 assembly forms a 1:1:1 ternary complex [PMID:22232181]. Ligand engagement of receptor-1 subunits is governed by a flexible region around residue T198 in IL-24, which controls binding affinity to IL-20R1 and IL-22R1 and signaling competence [PMID:31152679]. Within the heterodimer, IL-20R1 contributes the signal-transducing function, placing it upstream of JAK1–STAT3—but not JAK1–STAT1—signaling [PMID:34283251]. Through this axis IL-20RA drives diverse physiology: it is required for IL-20-mediated hepatic stellate cell activation and CCl4-induced liver fibrosis [PMID:24763901], activates a JAK1–STAT3–SOX2 program that enhances cancer stemness and induces PD-L1 while remodeling the immune microenvironment in breast cancer [PMID:33456560], and mediates rIL-19-driven CD163 scavenger-receptor upregulation and hematoma resolution via an IL-20R1/ERK/Nrf2 pathway [PMID:33532035]. IL-20RA expression is itself regulated post-transcriptionally by miR-452 [PMID:34283251] and through a distal NF-κB-bound regulatory element near TNFAIP3 that loops to the IL-20RA locus [PMID:29483615], and it contributes to leukocyte transmigration across intestinal lymphatic endothelium in Crohn's disease [PMID:31426584].","teleology":[{"year":2001,"claim":"Established which receptor complexes transduce IL-24/IL-20 signals, defining IL-20R1 as a shared signaling subunit that activates STATs upon ligand binding.","evidence":"Ligand binding saturation kinetics in transfected COS cells and STAT activation assays in keratinocytes and BHK cells","pmids":["11706020"],"confidence":"High","gaps":["Did not resolve the relative contributions of IL-20R1 versus IL-20R2 to ligand capture vs signal transduction","No structural basis for heterodimer assembly"]},{"year":2011,"claim":"Defined the stoichiometry of the signaling complex by purifying and crystallizing a 1:1:1 IL-20/IL-20R1/IL-20R2 ternary assembly.","evidence":"Protein purification, crystallization, and preliminary X-ray diffraction to 3 Å","pmids":["22232181"],"confidence":"Medium","gaps":["No full refined structure reported in this work","Interface residues mediating receptor assembly not yet mapped"]},{"year":2014,"claim":"Demonstrated a required in vivo role for IL-20R1 in disease by showing it drives IL-20-mediated hepatic stellate cell activation and liver fibrosis.","evidence":"IL-20R1-deficient mice, anti-IL-20R1 antibody blockade, and in vitro HSC assays in a CCl4 liver injury model","pmids":["24763901"],"confidence":"High","gaps":["Downstream transcription factors in HSCs not specified","Cell-type-specific receptor requirement (HSC vs hepatocyte) not dissected genetically"]},{"year":2018,"claim":"Identified a distal cis-regulatory mechanism controlling IL-20RA expression, linking an autoimmune risk variant to receptor levels.","evidence":"CRISPR/Cas9 deletion in HEK293T, EMSA, and 3C chromatin conformation capture of an element ~140 kb upstream of TNFAIP3","pmids":["29483615"],"confidence":"Medium","gaps":["Physiological cell types where this looping operates not defined","Functional consequence of altered IL-20RA dose on signaling output not measured"]},{"year":2019,"claim":"Mapped the ligand determinant governing receptor-1 engagement, showing residue T198 in IL-24 dictates IL-20R1/IL-22R1 binding affinity and signaling.","evidence":"PROSS-based protein engineering, biophysical binding to receptor ectodomains, signaling assays, and crystal structure (PDB 6GG1)","pmids":["31152679"],"confidence":"High","gaps":["Corresponding receptor-side binding residues on IL-20R1 not resolved","Does not address IL-19/IL-20 binding determinants"]},{"year":2019,"claim":"Implicated IL-20RA intracellular signaling in pathological leukocyte trafficking across lymphatic endothelium in Crohn's disease.","evidence":"Transcriptomics of human intestinal lymphatic endothelial cells, transwell transmigration assay, and mTOR pathway manipulation","pmids":["31426584"],"confidence":"Medium","gaps":["Downstream signaling effectors in endothelial cells not defined","Ligand driving the response not identified"]},{"year":2021,"claim":"Connected IL-20RA to cancer stemness and immune evasion through a JAK1–STAT3–SOX2 axis and PD-L1 induction.","evidence":"Gain- and loss-of-function in breast cancer cell lines and mouse models with flow cytometry and in vivo tumor assays","pmids":["33456560"],"confidence":"Medium","gaps":["Ligand driving tumor-cell IL-20RA signaling not defined","Single-lab in vivo validation"]},{"year":2021,"claim":"Placed IL-20RA upstream of JAK1–STAT3 (but not STAT1) and identified miR-452 as a direct post-transcriptional regulator in colorectal cancer.","evidence":"Luciferase 3'UTR reporter, siRNA knockdown, Western blot, and RT-PCR","pmids":["34283251"],"confidence":"Medium","gaps":["Mechanistic basis for STAT3 vs STAT1 selectivity not resolved","In vivo relevance of miR-452/IL-20RA axis not tested"]},{"year":2021,"claim":"Revealed an ERK/Nrf2 branch of IL-20R1 signaling driving CD163 scavenger-receptor upregulation and hematoma resolution.","evidence":"Rat germinal matrix hemorrhage model with rIL-19 treatment, IL-20R1 CRISPR knockdown, and immunohistochemistry","pmids":["33532035"],"confidence":"Medium","gaps":["Whether ERK/Nrf2 acts independently of JAK–STAT not clarified","Single-lab in vivo model"]},{"year":2022,"claim":"Refined the division of labor within the heterodimer in a fish ortholog, with IL-20R2 capturing ligand and IL-20R1 transducing STAT3 phosphorylation.","evidence":"Co-immunoprecipitation, STAT3 phosphorylation assay, and structural modeling in grass carp","pmids":["36414129"],"confidence":"Medium","gaps":["Non-mammalian model; mammalian receptor labor division not directly retested","Co-IP not reciprocally validated for human receptors"]},{"year":2024,"claim":"Extended the receptor-1 transducer role to IL-26 signaling and mucosal barrier protection in a fish ortholog.","evidence":"Co-immunoprecipitation, RNAi knockdown of IL20R1, JAK1–STAT3 readout, and in vivo bacterial challenge in crucian carp hybrid","pmids":["39154973"],"confidence":"Medium","gaps":["IL-26/IL-20R1 interaction not demonstrated for the human receptor","Single-lab non-mammalian system"]},{"year":2024,"claim":"Linked IL-20RA to mitochondrial antioxidant capacity in pig Sertoli cells.","evidence":"siRNA knockdown with ROS, mitochondrial superoxide, catalase, and transcriptomic readouts","pmids":["39765872"],"confidence":"Low","gaps":["Single-method knockdown without rescue or pathway dissection","Non-human cells; mechanism linking receptor to mitochondria undefined"]},{"year":2025,"claim":"Associated IL-20RA with apoptosis/ferroptosis suppression and STAT3/SNAIL-driven EMT in Wilms tumor cells.","evidence":"siRNA knockdown with apoptosis, ferroptosis, and EMT marker analysis","pmids":["40185911"],"confidence":"Low","gaps":["Pathway placement inferred without full mechanistic validation","Abstract-level description; not independently confirmed"]},{"year":null,"claim":"A high-resolution structure of the assembled signaling heterodimer and the molecular basis for IL-20R1's STAT3-over-STAT1 selectivity remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No refined full structure of the ternary signaling complex reported","Determinants of STAT3 vs STAT1 bias not mechanistically defined","Receptor-side ligand-binding residues on IL-20R1 not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,9]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,7]}],"complexes":["IL-20R1/IL-20R2 receptor complex","IL-22R1/IL-20R2 receptor complex"],"partners":["IL20RB","IL22RA1","IL24","IL20","IL19","JAK1","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHF4","full_name":"Interleukin-20 receptor subunit alpha","aliases":["Cytokine receptor class-II member 8","Cytokine receptor family 2 member 8","CRF2-8","IL-20R1","ZcytoR7"],"length_aa":553,"mass_kda":62.5,"function":"The IL20RA/IL20RB dimer is a receptor for IL19, IL20 and IL24. The IL20RA/IL10RB dimer is a receptor for IL26","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UHF4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL20RA","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL20RA","total_profiled":1310},"omim":[{"mim_id":"606648","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-2; IL22RA2","url":"https://www.omim.org/entry/606648"},{"mim_id":"605679","title":"INTERLEUKIN 26; IL26","url":"https://www.omim.org/entry/605679"},{"mim_id":"605621","title":"INTERLEUKIN 20 RECEPTOR, BETA; IL20RB","url":"https://www.omim.org/entry/605621"},{"mim_id":"605620","title":"INTERLEUKIN 20 RECEPTOR, ALPHA; IL20RA","url":"https://www.omim.org/entry/605620"},{"mim_id":"605619","title":"INTERLEUKIN 20; IL20","url":"https://www.omim.org/entry/605619"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"breast","ntpm":24.8},{"tissue":"skin 1","ntpm":35.5}],"url":"https://www.proteinatlas.org/search/IL20RA"},"hgnc":{"alias_symbol":["ZCYTOR7","IL-20R1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UHF4","domains":[{"cath_id":"2.60.40.10","chopping":"34-130","consensus_level":"high","plddt":92.8612,"start":34,"end":130},{"cath_id":"2.60.40.10","chopping":"142-242","consensus_level":"high","plddt":93.5982,"start":142,"end":242},{"cath_id":"1.20.5","chopping":"254-279","consensus_level":"medium","plddt":89.6723,"start":254,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF4-F1-predicted_aligned_error_v6.png","plddt_mean":62.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL20RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL20RA"},"sequence":{"accession":"Q9UHF4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHF4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHF4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF4"}},"corpus_meta":[{"pmid":"11706020","id":"PMC_11706020","title":"Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11706020","citation_count":225,"is_preprint":false},{"pmid":"33456560","id":"PMC_33456560","title":"IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33456560","citation_count":77,"is_preprint":false},{"pmid":"27799070","id":"PMC_27799070","title":"Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23.","date":"2016","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/27799070","citation_count":72,"is_preprint":false},{"pmid":"24763901","id":"PMC_24763901","title":"IL-20 and IL-20R1 antibodies protect against liver fibrosis.","date":"2014","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24763901","citation_count":65,"is_preprint":false},{"pmid":"34336707","id":"PMC_34336707","title":"Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34336707","citation_count":34,"is_preprint":false},{"pmid":"29483615","id":"PMC_29483615","title":"CRISPR/cas9 mediated knockout of an intergenic variant rs6927172 identified IL-20RA as a new risk gene for multiple autoimmune diseases.","date":"2018","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29483615","citation_count":23,"is_preprint":false},{"pmid":"34283251","id":"PMC_34283251","title":"MicroRNA 452 regulates IL20RA-mediated JAK1/STAT3 pathway in inflammatory colitis and colorectal cancer.","date":"2021","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/34283251","citation_count":22,"is_preprint":false},{"pmid":"18480827","id":"PMC_18480827","title":"Association analysis of IL20RA and IL20RB genes in psoriasis.","date":"2008","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18480827","citation_count":22,"is_preprint":false},{"pmid":"31152679","id":"PMC_31152679","title":"Flexible regions govern promiscuous binding of IL-24 to receptors IL-20R1 and IL-22R1.","date":"2019","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/31152679","citation_count":19,"is_preprint":false},{"pmid":"31426584","id":"PMC_31426584","title":"mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn's Disease.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31426584","citation_count":13,"is_preprint":false},{"pmid":"39154973","id":"PMC_39154973","title":"Fish IL-26 collaborates with IL-10R2 and IL-20R1 to enhance gut mucosal barrier during the antibacterial innate immunity.","date":"2024","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39154973","citation_count":9,"is_preprint":false},{"pmid":"36414129","id":"PMC_36414129","title":"Grass carp IL-20 binds to IL-20R2 but induces STAT3 phosphorylation via IL-20R1.","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36414129","citation_count":6,"is_preprint":false},{"pmid":"33532035","id":"PMC_33532035","title":"IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/33532035","citation_count":6,"is_preprint":false},{"pmid":"39875436","id":"PMC_39875436","title":"Programmed cell death-related gene IL20RA facilitates tumor progression and remodels tumor microenvironment in thyroid cancer.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39875436","citation_count":5,"is_preprint":false},{"pmid":"23811545","id":"PMC_23811545","title":"Detection of IL-20R1 and IL-20R2 mRNA in C57BL/6 mice astroglial cells and brain cortex following LPS stimulation.","date":"2013","source":"Iranian journal of immunology : IJI","url":"https://pubmed.ncbi.nlm.nih.gov/23811545","citation_count":4,"is_preprint":false},{"pmid":"39712242","id":"PMC_39712242","title":"IL-20RA is Associated with the Risk of Diabetic Microangiopathy: A Bidirectional Mendelian Randomization Analysis and Clinical Validation.","date":"2024","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39712242","citation_count":2,"is_preprint":false},{"pmid":"40185911","id":"PMC_40185911","title":"The signature based on interleukin family and receptors identified IL19 and IL20RA in promoting nephroblastoma progression through STAT3 pathway.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40185911","citation_count":1,"is_preprint":false},{"pmid":"22232181","id":"PMC_22232181","title":"Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex.","date":"2011","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22232181","citation_count":0,"is_preprint":false},{"pmid":"39765872","id":"PMC_39765872","title":"IL20RA Is the Key Factor Contributing to the Stronger Antioxidant Capacity of Rongchang Pig Sertoli Cells.","date":"2024","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39765872","citation_count":0,"is_preprint":false},{"pmid":"40989758","id":"PMC_40989758","title":"Downregulation of IL-20RA in Cerebrospinal Fluid Associated with the Risk of Moyamoya Disease: A Molecular Signatures Analysis with an Inflammation Proteomics Landscape.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40989758","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.22.24315951","title":"Genetically Predicted Inflammatory Proteins Mediate the Association Between Gut Microbiota and Preterm Delivery: A Mendelian Randomization Study","date":"2024-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.22.24315951","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13095,"output_tokens":3424,"usd":0.045323,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10988,"output_tokens":4045,"usd":0.078033,"stage2_stop_reason":"end_turn"},"total_usd":0.123356,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-24 (MDA-7/MOB-5) binds to and signals through two heterodimeric receptor complexes: IL-22R1/IL-20R2 and IL-20R1/IL-20R2 (the latter being the same receptor used by IL-20). COS cells transfected with either receptor heterodimer bind IL-24 with similar saturation kinetics, and IL-24 binding to either receptor complex on keratinocytes or ectopically expressing BHK cells activates STAT transcription factors.\",\n      \"method\": \"Ligand binding assay (COS cell transfection, saturation kinetics), STAT activation assay in keratinocytes and BHK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated in multiple cell contexts, STAT activation confirmed, replicated across cell types in a single rigorous study\",\n      \"pmids\": [\"11706020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The IL-20–IL-20R1–IL-20R2 ternary complex was successfully purified and crystallized, forming a 1:1:1 complex that diffracted to 3 Å resolution, establishing the stoichiometry and feasibility of structural determination of the IL-20/IL-20R1/IL-20R2 signaling complex.\",\n      \"method\": \"Protein purification, crystallization, preliminary X-ray diffraction analysis\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology and crystallization communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure reported at preliminary stage (no full structure published in this abstract), single study\",\n      \"pmids\": [\"22232181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-20 signals through IL-20R1-containing receptor complexes to activate hepatic stellate cells, upregulate TGF-β1, TNF-α, and type I collagen expression, promote HSC proliferation and migration, and induce hepatocyte cell-cycle arrest. IL-20R1-deficient mice were protected from both short-term and long-term CCl4-induced liver injury, establishing IL-20R1 as required for IL-20-mediated hepatic fibrosis.\",\n      \"method\": \"Anti-IL-20R1 monoclonal antibody (51D) treatment in vivo; IL-20R1-deficient mouse model; in vitro HSC activation assays; CCl4 liver injury model\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout (IL-20R1-deficient mice) combined with antibody blockade and in vitro functional assays across multiple cell types and in vivo models\",\n      \"pmids\": [\"24763901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-24 binding to receptor 1 subunits (IL-20R1 and IL-22R1) is governed by a flexible region around residue T198 in IL-24; a single back-engineered wild-type residue (T198) restored 80% of binding affinity to IL-20R1 and IL-22R1 and restored signaling capacity, while affinity to IL-20R2 was preserved in stabilized IL-24 variants.\",\n      \"method\": \"Protein engineering (PROSS algorithm-based mutagenesis), biophysical binding assays to extracellular receptor domains, signaling capacity assay, crystal structure of IL-24 variant (PDB 6GG1)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure determination plus site-directed mutagenesis with functional rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31152679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In intestinal lymphatic endothelial cells from Crohn's disease patients, mTOR signaling drives upregulation of IL-20RA, and IL-20RA-mediated intracellular signaling is required for LPMC transmigration through the lymphatic endothelial barrier; blocking this pathway reduced leukocyte trafficking.\",\n      \"method\": \"Transcriptomic profiling of isolated human intestinal lymphatic endothelial cells, transwell co-culture transmigration assay, mTOR pathway manipulation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional transmigration assay with pathway inhibition, single lab, human primary cells\",\n      \"pmids\": [\"31426584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-20RA activates the JAK1–STAT3–SOX2 signaling axis in breast cancer cells, enhancing stemness (increased SP proportion, ALDH activity, sphere formation, Sox2/Oct4 expression) and promoting PD-L1 expression while reducing CD8+ T cell and NK cell recruitment and increasing MDSC proportions in the tumor microenvironment.\",\n      \"method\": \"Gain- and loss-of-function (overexpression and knockdown) in breast cancer cell lines and mouse models; ELISA; flow cytometry; in vivo tumor initiation and metastasis assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with multiple orthogonal phenotypic readouts and in vivo validation, single lab\",\n      \"pmids\": [\"33456560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MIR452 directly targets IL-20RA (confirmed by luciferase reporter assay); overexpression of MIR452 decreases IL-20RA protein and downstream JAK1 and STAT3 (but not STAT1), and IL-20RA knockdown similarly decreases JAK1 and STAT3, placing IL-20RA upstream of JAK1–STAT3 (but not JAK1–STAT1) signaling in colorectal cancer cells.\",\n      \"method\": \"Luciferase reporter assay (miR-452 targeting IL-20RA 3'UTR), siRNA knockdown, Western blot, RT-PCR\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase assay plus knockdown with defined downstream pathway readouts, single lab\",\n      \"pmids\": [\"34283251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-20R1 mediates hematoma resolution after germinal matrix hemorrhage via the IL-20R1/ERK/Nrf2 pathway: rIL-19 treatment upregulated ERK, Nrf2, and CD163 expression, while IL-20R1 CRISPR knockdown abolished these effects, demonstrating that IL-20R1 is required for rIL-19-mediated scavenger receptor CD163 upregulation.\",\n      \"method\": \"In vivo rat GMH model; intranasal rIL-19 administration; IL-20R1 CRISPR knockdown (intracerebroventricular); Western blot; immunohistochemistry; hemoglobin assay; neurobehavioral testing\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown (CRISPR) of IL-20R1 with rescue/blockade, multiple outcome measures, single lab in vivo model\",\n      \"pmids\": [\"33532035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRISPR/Cas9 deletion of a genomic region containing variant rs6927172 (located ~140 kb upstream of TNFAIP3) altered expression of IL-20RA; EMSA and chromatin conformation capture demonstrated that the DNA element carrying rs6927172 physically interacts with the IL-20RA locus and that the risk allele enhances NFκB binding and chromatin looping to regulate IL-20RA expression.\",\n      \"method\": \"CRISPR/Cas9 knockout in HEK293T cells, EMSA, Western blot, chromatin conformation capture (3C), TALE-based transcriptional analysis\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (CRISPR deletion, EMSA, 3C chromatin looping) establishing regulatory mechanism, single lab\",\n      \"pmids\": [\"29483615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In grass carp, IL-20R1 (CiIL-20R1/CRFB8) but not IL-20R2 is responsible for STAT3 phosphorylation downstream of IL-20 signaling; co-immunoprecipitation showed that IL-20 binds CiIL-20R2 but not CiIL-20R1, suggesting a division of labor where R2 captures ligand and R1 transduces the intracellular STAT3 signal. Structural modeling showed conservation of key residues with human IL-20R1.\",\n      \"method\": \"Co-immunoprecipitation, STAT3 phosphorylation assay, structural modeling\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and functional signaling assay in fish ortholog with structural conservation noted; single lab, non-mammalian model\",\n      \"pmids\": [\"36414129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In fish (crucian carp hybrid), WR-IL-26 forms a complex with both WR-IL10R2 and WR-IL20R1 (co-immunoprecipitation); silencing WR-IL20R1 via RNA interference significantly attenuated IL-26-mediated JAK1–STAT3 pathway activation and reduced gut mucosal barrier protection against Aeromonas hydrophila infection.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference knockdown, JAK1–STAT3 signaling assay, in vivo bacterial challenge\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus RNAi loss-of-function with defined signaling readout, single lab, non-mammalian model (fish ortholog)\",\n      \"pmids\": [\"39154973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-20RA knockdown in nephroblastoma (Wilms tumor) cells increased apoptosis and ferroptosis, and IL-20RA promotes epithelial-mesenchymal transition through the STAT3/SNAIL pathway.\",\n      \"method\": \"siRNA knockdown, apoptosis/ferroptosis assays, EMT marker analysis, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with phenotypic readout, pathway placement inferred without full mechanistic validation; abstract-level description\",\n      \"pmids\": [\"40185911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pig Sertoli cells, IL-20RA knockdown (siRNA) affected mitochondrial superoxide production and catalase secretion, identifying IL-20RA as a regulator of mitochondrial antioxidant capacity in these cells.\",\n      \"method\": \"siRNA knockdown, ROS measurement, mitochondrial superoxide assay, catalase activity assay, transcriptomic analysis\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method knockdown in non-human (pig) cells, single lab, limited mechanistic pathway detail in abstract\",\n      \"pmids\": [\"39765872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-20RA (IL-20R1/ZCYTOR7) is a cytokine receptor subunit that forms heterodimeric signaling complexes with IL-20R2 (binding IL-19, IL-20, and IL-24) and with IL-22R1 (binding IL-24); upon ligand binding, IL-20R1 provides the long intracellular domain responsible for activating JAK1–STAT3 (and to a lesser extent STAT1) signaling, driving downstream transcriptional programs including SOX2, PD-L1, and Nrf2 in contexts ranging from skin and liver homeostasis to cancer stemness, immune regulation, and inflammatory disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL20RA (IL-20R1/ZCYTOR7) is a cytokine receptor subunit that assembles heterodimeric signaling complexes to transduce IL-19, IL-20, and IL-24 family signals into JAK1–STAT3 transcriptional programs governing epithelial homeostasis, inflammation, and tumor biology [#0, #5]. It pairs with IL-20R2 to form ligand-binding heterodimers: IL-24 signals through both IL-20R1/IL-20R2 and IL-22R1/IL-20R2 complexes, with IL-20R1 binding ligand and activating STAT transcription factors in keratinocytes and other cells [#0], and the IL-20/IL-20R1/IL-20R2 assembly forms a 1:1:1 ternary complex [#1]. Ligand engagement of receptor-1 subunits is governed by a flexible region around residue T198 in IL-24, which controls binding affinity to IL-20R1 and IL-22R1 and signaling competence [#3]. Within the heterodimer, IL-20R1 contributes the signal-transducing function, placing it upstream of JAK1–STAT3—but not JAK1–STAT1—signaling [#6]. Through this axis IL-20RA drives diverse physiology: it is required for IL-20-mediated hepatic stellate cell activation and CCl4-induced liver fibrosis [#2], activates a JAK1–STAT3–SOX2 program that enhances cancer stemness and induces PD-L1 while remodeling the immune microenvironment in breast cancer [#5], and mediates rIL-19-driven CD163 scavenger-receptor upregulation and hematoma resolution via an IL-20R1/ERK/Nrf2 pathway [#7]. IL-20RA expression is itself regulated post-transcriptionally by miR-452 [#6] and through a distal NF-κB-bound regulatory element near TNFAIP3 that loops to the IL-20RA locus [#8], and it contributes to leukocyte transmigration across intestinal lymphatic endothelium in Crohn's disease [#4].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established which receptor complexes transduce IL-24/IL-20 signals, defining IL-20R1 as a shared signaling subunit that activates STATs upon ligand binding.\",\n      \"evidence\": \"Ligand binding saturation kinetics in transfected COS cells and STAT activation assays in keratinocytes and BHK cells\",\n      \"pmids\": [\"11706020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the relative contributions of IL-20R1 versus IL-20R2 to ligand capture vs signal transduction\", \"No structural basis for heterodimer assembly\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the stoichiometry of the signaling complex by purifying and crystallizing a 1:1:1 IL-20/IL-20R1/IL-20R2 ternary assembly.\",\n      \"evidence\": \"Protein purification, crystallization, and preliminary X-ray diffraction to 3 Å\",\n      \"pmids\": [\"22232181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full refined structure reported in this work\", \"Interface residues mediating receptor assembly not yet mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a required in vivo role for IL-20R1 in disease by showing it drives IL-20-mediated hepatic stellate cell activation and liver fibrosis.\",\n      \"evidence\": \"IL-20R1-deficient mice, anti-IL-20R1 antibody blockade, and in vitro HSC assays in a CCl4 liver injury model\",\n      \"pmids\": [\"24763901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcription factors in HSCs not specified\", \"Cell-type-specific receptor requirement (HSC vs hepatocyte) not dissected genetically\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a distal cis-regulatory mechanism controlling IL-20RA expression, linking an autoimmune risk variant to receptor levels.\",\n      \"evidence\": \"CRISPR/Cas9 deletion in HEK293T, EMSA, and 3C chromatin conformation capture of an element ~140 kb upstream of TNFAIP3\",\n      \"pmids\": [\"29483615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological cell types where this looping operates not defined\", \"Functional consequence of altered IL-20RA dose on signaling output not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped the ligand determinant governing receptor-1 engagement, showing residue T198 in IL-24 dictates IL-20R1/IL-22R1 binding affinity and signaling.\",\n      \"evidence\": \"PROSS-based protein engineering, biophysical binding to receptor ectodomains, signaling assays, and crystal structure (PDB 6GG1)\",\n      \"pmids\": [\"31152679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Corresponding receptor-side binding residues on IL-20R1 not resolved\", \"Does not address IL-19/IL-20 binding determinants\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated IL-20RA intracellular signaling in pathological leukocyte trafficking across lymphatic endothelium in Crohn's disease.\",\n      \"evidence\": \"Transcriptomics of human intestinal lymphatic endothelial cells, transwell transmigration assay, and mTOR pathway manipulation\",\n      \"pmids\": [\"31426584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling effectors in endothelial cells not defined\", \"Ligand driving the response not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected IL-20RA to cancer stemness and immune evasion through a JAK1–STAT3–SOX2 axis and PD-L1 induction.\",\n      \"evidence\": \"Gain- and loss-of-function in breast cancer cell lines and mouse models with flow cytometry and in vivo tumor assays\",\n      \"pmids\": [\"33456560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving tumor-cell IL-20RA signaling not defined\", \"Single-lab in vivo validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed IL-20RA upstream of JAK1–STAT3 (but not STAT1) and identified miR-452 as a direct post-transcriptional regulator in colorectal cancer.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, siRNA knockdown, Western blot, and RT-PCR\",\n      \"pmids\": [\"34283251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis for STAT3 vs STAT1 selectivity not resolved\", \"In vivo relevance of miR-452/IL-20RA axis not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an ERK/Nrf2 branch of IL-20R1 signaling driving CD163 scavenger-receptor upregulation and hematoma resolution.\",\n      \"evidence\": \"Rat germinal matrix hemorrhage model with rIL-19 treatment, IL-20R1 CRISPR knockdown, and immunohistochemistry\",\n      \"pmids\": [\"33532035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ERK/Nrf2 acts independently of JAK–STAT not clarified\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined the division of labor within the heterodimer in a fish ortholog, with IL-20R2 capturing ligand and IL-20R1 transducing STAT3 phosphorylation.\",\n      \"evidence\": \"Co-immunoprecipitation, STAT3 phosphorylation assay, and structural modeling in grass carp\",\n      \"pmids\": [\"36414129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-mammalian model; mammalian receptor labor division not directly retested\", \"Co-IP not reciprocally validated for human receptors\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the receptor-1 transducer role to IL-26 signaling and mucosal barrier protection in a fish ortholog.\",\n      \"evidence\": \"Co-immunoprecipitation, RNAi knockdown of IL20R1, JAK1–STAT3 readout, and in vivo bacterial challenge in crucian carp hybrid\",\n      \"pmids\": [\"39154973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IL-26/IL-20R1 interaction not demonstrated for the human receptor\", \"Single-lab non-mammalian system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked IL-20RA to mitochondrial antioxidant capacity in pig Sertoli cells.\",\n      \"evidence\": \"siRNA knockdown with ROS, mitochondrial superoxide, catalase, and transcriptomic readouts\",\n      \"pmids\": [\"39765872\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method knockdown without rescue or pathway dissection\", \"Non-human cells; mechanism linking receptor to mitochondria undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Associated IL-20RA with apoptosis/ferroptosis suppression and STAT3/SNAIL-driven EMT in Wilms tumor cells.\",\n      \"evidence\": \"siRNA knockdown with apoptosis, ferroptosis, and EMT marker analysis\",\n      \"pmids\": [\"40185911\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred without full mechanistic validation\", \"Abstract-level description; not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the assembled signaling heterodimer and the molecular basis for IL-20R1's STAT3-over-STAT1 selectivity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No refined full structure of the ternary signaling complex reported\", \"Determinants of STAT3 vs STAT1 bias not mechanistically defined\", \"Receptor-side ligand-binding residues on IL-20R1 not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [\n      \"IL-20R1/IL-20R2 receptor complex\",\n      \"IL-22R1/IL-20R2 receptor complex\"\n    ],\n    \"partners\": [\n      \"IL20RB\",\n      \"IL22RA1\",\n      \"IL24\",\n      \"IL20\",\n      \"IL19\",\n      \"JAK1\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}